JPH03271224A - Carcinostatic agent - Google Patents
Carcinostatic agentInfo
- Publication number
- JPH03271224A JPH03271224A JP6398590A JP6398590A JPH03271224A JP H03271224 A JPH03271224 A JP H03271224A JP 6398590 A JP6398590 A JP 6398590A JP 6398590 A JP6398590 A JP 6398590A JP H03271224 A JPH03271224 A JP H03271224A
- Authority
- JP
- Japan
- Prior art keywords
- column chromatography
- water
- phase system
- ethanol
- rhamnopyranosyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000003327 cancerostatic effect Effects 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 11
- 238000004440 column chromatography Methods 0.000 abstract description 8
- HDXIQHTUNGFJIC-UHFFFAOYSA-N (25R)-spirost-5-en-3beta-ol 3-O-<O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-glucopyranoside> Natural products O1C2(OCC(C)CC2)C(C)C(C2(CCC3C4(C)CC5)C)C1CC2C3CC=C4CC5OC1OC(CO)C(O)C(O)C1OC1OC(C)C(O)C(O)C1O HDXIQHTUNGFJIC-UHFFFAOYSA-N 0.000 abstract description 6
- VNONINPVFQTJOC-RXEYMUOJSA-N Collettiside III Natural products O([C@@H]1[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@H](O)[C@@H](O)[C@H](C)O2)[C@H](CO)O[C@@H]1O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]5[C@H](C)[C@@]6(O[C@H]5C4)OC[C@H](C)CC6)CC3)CC=2)CC1)[C@H]1[C@H](O)[C@H](O)[C@@H](O)[C@H](C)O1 VNONINPVFQTJOC-RXEYMUOJSA-N 0.000 abstract description 6
- VNONINPVFQTJOC-ZGXDEBHDSA-N dioscin Chemical compound O([C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)O[C@H]1[C@@H]([C@H](O)[C@@H](O)[C@H](C)O1)O)O[C@@H]1CC2=CC[C@H]3[C@@H]4C[C@H]5[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@@H]([C@]1(OC[C@H](C)CC1)O5)C)[C@@H]1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O VNONINPVFQTJOC-ZGXDEBHDSA-N 0.000 abstract description 6
- CJNUQCDDINHHHD-APRUHSSNSA-N dioscin Natural products C[C@@H]1CC[C@@]2(OC1)O[C@H]3C[C@H]4[C@@H]5CC=C6C[C@H](CC[C@@H]6[C@H]5CC[C@]4(C)[C@H]3[C@@H]2C)O[C@@H]7O[C@H](CO)[C@@H](O[C@@H]8O[C@@H](C)[C@H](O)[C@@H](O)[C@H]8O)[C@H](O)[C@H]7O[C@@H]9O[C@@H](C)[C@H](O)[C@@H](O)[C@H]9O CJNUQCDDINHHHD-APRUHSSNSA-N 0.000 abstract description 6
- VNONINPVFQTJOC-UHFFFAOYSA-N polyphyllin III Natural products O1C2(OCC(C)CC2)C(C)C(C2(CCC3C4(C)CC5)C)C1CC2C3CC=C4CC5OC(C(C1O)OC2C(C(O)C(O)C(C)O2)O)OC(CO)C1OC1OC(C)C(O)C(O)C1O VNONINPVFQTJOC-UHFFFAOYSA-N 0.000 abstract description 6
- 239000000284 extract Substances 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 239000012046 mixed solvent Substances 0.000 abstract description 2
- 230000035755 proliferation Effects 0.000 abstract description 2
- 241000907616 Dioscorea tokoro Species 0.000 abstract 2
- 235000016420 Dioscorea tokoro Nutrition 0.000 abstract 2
- 241000234272 Dioscoreaceae Species 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 3
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 description 3
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 3
- 239000004166 Lanolin Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 235000019388 lanolin Nutrition 0.000 description 3
- 229940039717 lanolin Drugs 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 239000004952 Polyamide Substances 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920002647 polyamide Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- DWCSNWXARWMZTG-UHFFFAOYSA-N Trigonegenin A Natural products CC1C(C2(CCC3C4(C)CCC(O)C=C4CCC3C2C2)C)C2OC11CCC(C)CO1 DWCSNWXARWMZTG-UHFFFAOYSA-N 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 208000015322 bone marrow disease Diseases 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- WQLVFSAGQJTQCK-VKROHFNGSA-N diosgenin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 WQLVFSAGQJTQCK-VKROHFNGSA-N 0.000 description 1
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- -1 pleomycin Chemical compound 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔技術分野〕
本発明は新規な制癌剤に関するものである。さらに詳し
く言えば２本発明は式
で表される化合物を有効成分として含有する制癌剤に関
するものである。DETAILED DESCRIPTION OF THE INVENTION [Technical Field] The present invention relates to a novel anticancer agent. More specifically, the present invention relates to an anticancer agent containing a compound represented by the formula as an active ingredient.
近年、癌は日本人の死亡原因の第−位を占め、また世界
先進諸国においても同じ傾向が認められ癌制圧は人類の
悲願ともいえる命題である。現在、癌の治療は、外科的
治療、放射線治療、薬物治療が主に用いられている。薬
物治療では、化学療法剤及び免疫療法剤が主に用いられ
ている。化学療法剤としてはマイトマイシンＣ，プレオ
マイシン、５−フルオロウラシル、ドキソルビシン、メ
トトレキセート、シクロホスファミド、ビンクリスチン
等が知られているが、いずれも重篤な副作用、たとえば
骨髄障害、消化器障害、肝障害、腎障害等を伴うもので
ある。In recent years, cancer has become the leading cause of death among Japanese people, and the same trend has been observed in the developed countries of the world, making cancer control a fervent desire of humankind. Currently, surgical treatment, radiotherapy, and drug treatment are mainly used to treat cancer. In drug treatment, chemotherapeutic agents and immunotherapeutic agents are mainly used. Known chemotherapeutic agents include mitomycin C, pleomycin, 5-fluorouracil, doxorubicin, methotrexate, cyclophosphamide, and vincristine, but all of them have serious side effects, such as bone marrow disorders, gastrointestinal disorders, and liver disorders. , kidney damage, etc.
また、免疫療法剤としては、従来、サルノコシカケ科の
植物から単離した蛋白多糖体等が知られているが、近年
、効果の点において充分でないことが報ぜられている。In addition, as immunotherapeutic agents, protein polysaccharides and the like isolated from plants of the Arunococcaceae family have been known, but in recent years, it has been reported that they are not sufficiently effective.
このように、現在、制癌作用及び安全性の面で決定的な
制癌剤は見出されていないのが現状である。As described above, the current situation is that no definitive anticancer drug has been found in terms of anticancer activity and safety.
本発明者らは、癌制圧をテーマに、様々な角度から種々
の研究を進めてきたところ１式（Ｉ）で表される化合物
が強力な制癌活性を有し、安全域の広い前記式（１）で
表される化合物は１９０４年に本田によりヤマイモ科（
Ｄｉｏｓｃｏｒｅａｃａａｅ）のオニドコロ（Ｄｘｏｓ
ｃｏｒｅａ ｔｏｋｏｒｏ Ｍ＾ｘｔ）Ｉｏ）から単離
され、その後。The present inventors have carried out various studies from various angles with the theme of cancer control, and found that the compound represented by formula (I) has strong anticancer activity. The compound represented by (1) was discovered by Honda in 1904 in the family Yassimaceae (
Dioscoreacae)
corea tokoro M^xt) Io) and subsequently.
環水、川崎らにより構造研究がなされ、ジオスシン（Ｄ
ｉｏｓｃｉｎ）と命名されているが、制癌作用の報告は
全くない、前記式（Ｉ）で表される化合物は種々のクロ
マトグラフィーを用いて単離することができる。Structural research was conducted by Kansui, Kawasaki et al., and dioscin (D
The compound represented by the above formula (I), which is named as ioscin), but there are no reports of anticancer activity, can be isolated using various chromatography methods.
すなわち、オニドコロを水、エタノールあるいは水・エ
タノールの混合溶媒そ用いて抽出し、抽出液を濃縮後、
残留物を順相系のカラムクロマトグラフィー、例えば、
シリカゲルカラムクロマトグラフィー及び逆相系のカラ
ムクロマトグラフィー、例えば、ポリアミドカラムクロ
マトグラフィーを用いて精製し、さらに、順相系のカラ
ムクロマトグラフィー例えば、シリカゲルカラムクロマ
トグラフィーにて精製した後、メタノールから再結晶す
ることにより、前記式（１）で表される化合物を得るこ
とができた。That is, onidocoro is extracted using water, ethanol, or a mixed solvent of water and ethanol, and after concentrating the extract,
The residue is subjected to normal phase column chromatography, e.g.
After purification using silica gel column chromatography and reverse phase column chromatography, such as polyamide column chromatography, and further purification using normal phase column chromatography, such as silica gel column chromatography, recrystallization from methanol is performed. By doing so, a compound represented by the above formula (1) could be obtained.
以下に、式（Ｉ）のジオスシンの製造実施例を挙げる。Examples of the production of dioscin of formula (I) are given below.
各実施例で得られた化合物の物性値及び分析データにつ
いては実施例の後に挙げられている。また、化合物に関
する薬理作用、毒性、その他については後記の表１〜２
に挙げる。The physical property values and analytical data of the compounds obtained in each example are listed after the example. In addition, the pharmacological effects, toxicity, and other information regarding the compounds are listed in Tables 1 and 2 below.
Listed below.
〔実施例１〕
オニドコロ２００ｇをエタノール１党にて３０分間加熱
還流抽出する操作を２回繰り返す、抽出液を合わせ、減
圧下濃縮乾固する。残留物を水２００−に懸濁し、エー
テル５００−にて洗浄する６次に、水層を水飽和ｎ−ブ
タノール３００−にて３回抽出した後、抽出液を減圧下
濃縮乾固し、粗サポニン画分４３ｇを得る。[Example 1] The operation of heating and refluxing 200 g of Onidokoro with 1 part of ethanol for 30 minutes and extracting it was repeated twice. The extracts were combined and concentrated to dryness under reduced pressure. The residue was suspended in 200% of water and washed with 500% of ether.Next, the aqueous layer was extracted three times with 300% of water-saturated n-butanol, and the extract was concentrated to dryness under reduced pressure. 43 g of saponin fraction are obtained.
この画分４２ｇをシリカゲルカラムクロマトグラフィー
（キーセルゲル６０）に付し、クロロホルム・メタ／−
ル（８５：１５）で洗浄後、クロロホルム・メタノール
（８０：２０）で溶出する。溶出液を減圧下濃縮乾固後
、残留物７ｇをポリアミドカラムクロマトグラフィー（
Ｃ−２００）に付し、２０％エタノールで洗浄後、４０
％エタノールで溶出する。溶出液を減圧下濃縮乾固後、
残留物をシリカゲルカラムクロマトグラフィー（キーセ
ルゲル６０）に付し、クロロホルム・メタノール・水（
６０：ｔｏ：１）６００−を用いて洗浄後、クロロホル
ム・メタノール・水（６０：１０：１）４００−にて溶
出する。溶出液を減圧下ａ縮乾固後、残留物をメタノー
ルから繰返し再結晶することにより、 ３−Ｏ−（２−
０−α−１ラムノピラノシル−４−０−α−も一ラムノ
ピラノシル）〜β−０−グルコビラノシルジオスゲニン
（ジオスシン）１００ｍｇを得る。42 g of this fraction was subjected to silica gel column chromatography (Kiesel Gel 60), and chloroform meta/-
After washing with chloroform/methanol (80:20), elute with chloroform/methanol (80:20). After concentrating the eluate to dryness under reduced pressure, 7 g of the residue was subjected to polyamide column chromatography (
C-200) and washed with 20% ethanol.
Elute with % ethanol. After concentrating the eluate to dryness under reduced pressure,
The residue was subjected to silica gel column chromatography (Kiesel Gel 60) and chloroform/methanol/water (
After washing with chloroform/methanol/water (60:10:1) 600-, it is eluted with 400- chloroform/methanol/water (60:10:1). After condensing the eluate to dryness under reduced pressure, the residue was repeatedly recrystallized from methanol to give 3-O-(2-
100 mg of 0-α-1 rhamnopyranosyl-4-0-α-mono-rhamnopyranosyl) to β-0-glucobyranosyl diosgenin (dioscin) is obtained.
本発明に係る化合物の物性値及び分析データを示す。1 shows physical property values and analytical data of the compound according to the present invention.
（１） ３−Ｏ−（２−０−α−２−ラムノピラノシル
−４−０−α−２−ラムノピラノシル）−β−ｂ−グル
コピラノシルージオスゲニン（ジオスシン）の物性値及
び分析データｌ）性状及び溶解性
無色無臭の融点２９０〜２９５℃の針状結晶で、エタノ
ール、メタノール、ジメチルスルホキシド、ピリジンに
可溶で、ヘキサン、クロロホルム、ベンゼン、エーテル
、水に難溶である。(1) Physical properties and analytical data of 3-O-(2-0-α-2-rhamnopyranosyl-4-0-α-2-rhamnopyranosyl)-β-b-glucopyranosyldiosgenin (dioscin) l) Properties Solubility: Colorless and odorless needle-like crystals with a melting point of 290-295°C, soluble in ethanol, methanol, dimethyl sulfoxide, and pyridine, and sparingly soluble in hexane, chloroform, benzene, ether, and water.
２）赤外線吸収スペクトル（ＫＢｒ）分析３４２４．１
６４９．１０４２ ｃｍ−’に吸収の極大を示す。2) Infrared absorption spectrum (KBr) analysis 3424.1
It shows an absorption maximum at 649.1042 cm-'.
３）Ｈ１核磁気共鳴スペクトル（ｄＳ−ピリジン）分析 次のシグナルを示す（δ＋ ｐｐＩｌ）。3) H1 nuclear magnetic resonance spectrum (dS-pyridine) analysis The following signal is shown (δ+ppIl).
５．８４ （ＩＨ，−重線） （６位のＨ）５．３３
（ＬＨ，二重線、 Ｊ＝８．０Ｈｚ） （グルコース
の１位のＨ）
４．９４ （２Ｈ，多重線） （２個のラムノースの１
位のＨ）
３．６９ （２Ｈ，多重線）（２７位のＨ）１．７６
（３Ｈ，二重線、 Ｊ＝６．３） ’ｌ、 （２個のラ
ムノース１．６２ （３１（、、＝１ｍ、 Ｊ＝５．９
） Ｊ（７）６位、）Ｈ）１．１３ （３Ｂ、二重線、
Ｊ＝６．９） （２１位のメチル基のＨ）
１．０４ （３８，−重線）（１９位のメチル基のＨ）
０．８２ （３Ｈ，−重線）（１８位のメチル基のＨ）
０．６９ （３Ｈ，二重ｖＡ）（２６位ツメチル基（７
）Ｈ）４）１３Ｃ核磁気共鳴スペクトル（ｄ、−ピリジ
ン）分析
次のシグナルを示す（δ＋ ＰＰｒｎ）。5.84 (IH, - double line) (H at 6th position) 5.33
(LH, doublet, J=8.0Hz) (H at position 1 of glucose) 4.94 (2H, multiplet) (1 of two rhamnose
H at position) 3.69 (2H, multiplet) (H at position 27) 1.76
(3H, double line, J=6.3) 'l, (2 rhamnose 1.62 (31(,,=1m, J=5.9
) J (7) 6th place, ) H) 1.13 (3B, double line,
J=6.9) (H of methyl group at position 21) 1.04 (38, - double line) (H of methyl group at position 19)
0.82 (3H, - double line) (H of methyl group at position 18)
0.69 (3H, double vA) (26-position trimethyl group (7
) H) 4) 13C nuclear magnetic resonance spectrum (d,-pyridine) analysis shows the following signal (δ+ PPrn).
１４０．９９ （５位のＣ）
１２１．９’３ （６位のＣ）
１０９．４５ （２２位のＣ）
１０３．０８ （グルコースの１位のＣ）１０２．２
１．１００．４４ （ラムノースの１位のＣ）８１．
２９ （１６位のＣ）
７８．２８ （３位のＣ）
６７．０４ （２７位のＣ）
１５．２０ ！１
５）質量スペクトル分析
ｍ／ ｚ ８９１ （Ｍ＋１）’、 ４１５ （非糖
部＋１）“。140.99 (C at position 5) 121.9'3 (C at position 6) 109.45 (C at position 22) 103.08 (C at position 1 of glucose) 102.2
1.100.44 (Rhamnose 1st place C) 81.
29 (16th C) 78.28 (3rd C) 67.04 (27th C) 15.20! 1 5) Mass spectrum analysis m/z 891 (M+1)', 415 (non-sugar portion +1)''.
本発明に係る化合物の薬理作用および毒性についての実
験例を示す。Examples of experiments regarding the pharmacological action and toxicity of the compounds according to the present invention are shown.
〔実験例１〕
ガン細胞としてＬ１２１０白血病細胞（以下、Ｌ１２１
０と略す）を用いた。培地はセルグロッサ−Ｈ（目黒研
究所製）を使用し、この培地にてＬ１２１０細胞を８Ｘ
１０’個／ｍｌに調製して実験に用いた。この調製した
細胞浮遊液に各種濃度の被検薬物を加え培養後、３日、
５日及び７日における生細胞数をトリパンブルー染色法
を用いて計数し、対照群と薬物投与群のそれぞれの生細
胞数から被検薬物のＬ１２１０ｉ胞に対する増殖抑制率
を求め、ＩＣ１°値で示した。尚、被検薬物はジメチル
スルホキシドに溶解して用い、対照群ではジメチルスル
ホキシドのみを加えた。[Experimental Example 1] L1210 leukemia cells (hereinafter referred to as L121) were used as cancer cells.
0) was used. Cell Glosser-H (manufactured by Meguro Institute) was used as the medium, and L1210 cells were grown 8X in this medium.
It was prepared at 10' cells/ml and used in the experiment. After adding various concentrations of the test drug to the prepared cell suspension and culturing, for 3 days,
The number of viable cells on the 5th and 7th day was counted using the trypan blue staining method, and the growth inhibition rate of the test drug against L1210i cells was determined from the number of viable cells in the control group and the drug administration group, and the IC1 value was calculated. Indicated. The test drug was dissolved in dimethyl sulfoxide, and only dimethyl sulfoxide was added to the control group.
表１に示すように、本発明に係る化合物は強力なＬ１２
１０細胞増殖抑制作用を示すことが明らかとなった。As shown in Table 1, the compounds according to the present invention have a strong L12
It was revealed that this product exhibited an inhibitory effect on the proliferation of 10 cells.
〔実験例２〕 （毒性） 実験には、Ｓｔｄ：ｄｄＹ系雄性マウスを使用した。[Experiment Example 2] (Toxicity) Std:ddY male mice were used in the experiment.
被検薬物を３％アラビアゴム１０．９％生理食塩液に懸
濁し、皮下投与後、７２時間の致死数をから、Ｌｉｔｅ
ｈ−ｆｉｅｌｄ−Ｗｉｌｃｏｘｏｎ法に基づきＬＤ、
。値を算出した。結果を表２に示す。The test drug was suspended in 3% gum arabic and 10.9% physiological saline, and after subcutaneous administration, the number of fatalities was calculated for 72 hours.
LD based on the h-field-Wilcoxon method,
. The value was calculated. The results are shown in Table 2.
表２に示すように、本発明に係る化合物は３００ｍｇ／
ｋｇの投与量で死亡例は認められなかった。As shown in Table 2, the compound according to the present invention was
No deaths were observed at the kg dose.
以上、本発明に係る化合物は、ガン細胞増殖抑制作用を
有することが明らかとなった。As described above, it has been revealed that the compound according to the present invention has a cancer cell growth suppressive effect.
本発明に係る抗ガン剤の臨床投与量は、活性成分として
成人０．１〜５００１１１ｇ／日が好ましい１本発明の
製剤は任意所要の製剤用担体あるいは賦形剤により慣用
の方法で使用に供される。The clinical dosage of the anticancer agent according to the present invention is preferably 0.1 to 500,111 g/day for adults as the active ingredient. be done.
経口投与用の錠剤、散剤、顆粒剤、カプセル等は慣用の
賦形剤２例えば炭酸カルシウム、炭酸マグネシウム、リ
ン酸カルシウム、とうもろこしでんぷん、ばれいしょで
んぷん、砂糖、ラクトース、タルク、ステアリン酸マグ
ネシウム、アラビアゴム等を含有していてもよい１錠剤
は周知の方法でコーティングしてもよい、経口用液体製
剤は水性または油性懸濁液、溶液、シロップ、エリキシ
ル剤、その他であってもよ％Ｎ。Tablets, powders, granules, capsules, etc. for oral administration contain conventional excipients such as calcium carbonate, magnesium carbonate, calcium phosphate, corn starch, potato starch, sugar, lactose, talc, magnesium stearate, gum arabic, etc. The tablets may be coated in a well-known manner.Oral liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, etc.
注射用製剤は２本発明に係る化合物は用時溶解型が好ま
しい、また、懸濁化剤、安定剤または分散剤のような処
方剤を含んでいてもよく、滅菌蒸留水。Preparations for injection are preferably in the form of a compound according to the invention that is dissolved before use, and may also contain formulation agents such as suspending agents, stabilizing agents, or dispersing agents, and sterile distilled water.
精油たとえばビーナツツ油、とうもろこし油あるいは非
水溶媒、ポリエチレングリコール、ポリプロピレングリ
コール等を含有していてもよい。It may contain essential oils such as peanut oil, corn oil, or nonaqueous solvents, polyethylene glycol, polypropylene glycol, and the like.
直腸内投与のためには坐剤用組成物の形で提供され、当
業界において周知の製剤用担体２例えばポリエチレング
リコール、ラノリン、ココナツト油等を含有していても
よい。For rectal administration, it may be provided in the form of a suppository composition and may contain pharmaceutical carriers well known in the art, such as polyethylene glycol, lanolin, coconut oil, and the like.
局所適用のためには軟膏用組成物あるいは硬膏用組成物
の形で提供され、当業界において周知の製剤用担体１例
えばワセリン、パラフィン、加水ラノリン、プラスチベ
ース、ｖＡ水水上上セリンマクロゴール類ロウ、樹脂、
精製ラノリン、ゴムなどを含有していてもよい。For topical application, it may be provided in the form of ointment or plaster compositions, with pharmaceutical carriers well known in the art, such as vaseline, paraffin, hydrated lanolin, plastibase, vA water supraserine macrogol waxes, resin,
It may also contain purified lanolin, rubber, etc.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP02063985A JP3123745B2 (en) | 1990-03-16 | 1990-03-16 | Anticancer drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP02063985A JP3123745B2 (en) | 1990-03-16 | 1990-03-16 | Anticancer drug |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH03271224A true JPH03271224A (en) | 1991-12-03 |
| JP3123745B2 JP3123745B2 (en) | 2001-01-15 |
Family
ID=13245090
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP02063985A Expired - Lifetime JP3123745B2 (en) | 1990-03-16 | 1990-03-16 | Anticancer drug |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3123745B2 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100528663B1 (en) * | 2002-08-01 | 2005-11-15 | 경북대학교 산학협력단 | Composition containing dioscin for treatment or prevention of hyperlipidemia or arteriosclerosis |
| WO2008014564A1 (en) | 2006-08-03 | 2008-02-07 | Oncology Research International Limited | Methods and compositions for inhibiting angiogenesis |
| CN100439511C (en) * | 2006-11-07 | 2008-12-03 | 天津大学 | Process for catalytic extraction of yam saponin by using modified cellulase |
| US7906493B2 (en) | 2003-12-22 | 2011-03-15 | Btg International Limited | Core 2 GlcNAc-T inhibitors |
| US7998943B2 (en) | 2005-07-06 | 2011-08-16 | Btg International Limited | Core 2 GlcNAc-T inhibitors III |
| US8197794B2 (en) | 2003-12-22 | 2012-06-12 | Ms Therapeutics Limited | Core 2 GlcNAc-T inhibitors |
| US8609633B2 (en) | 2005-07-06 | 2013-12-17 | Ms Therapeutics Limited | Core 2 GlcNAc-T inhibitors |
| JP2015151344A (en) * | 2014-02-12 | 2015-08-24 | 株式会社アンチエイジング・プロ | Method for producing dioscorea japonica extract |
| WO2023040094A1 (en) * | 2021-09-18 | 2023-03-23 | 海南鑫开源医药科技有限公司 | Composition having effect of inhibition of tumor cell activity and application of composition |
-
1990
- 1990-03-16 JP JP02063985A patent/JP3123745B2/en not_active Expired - Lifetime
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100528663B1 (en) * | 2002-08-01 | 2005-11-15 | 경북대학교 산학협력단 | Composition containing dioscin for treatment or prevention of hyperlipidemia or arteriosclerosis |
| US7906493B2 (en) | 2003-12-22 | 2011-03-15 | Btg International Limited | Core 2 GlcNAc-T inhibitors |
| US8197794B2 (en) | 2003-12-22 | 2012-06-12 | Ms Therapeutics Limited | Core 2 GlcNAc-T inhibitors |
| US8609633B2 (en) | 2005-07-06 | 2013-12-17 | Ms Therapeutics Limited | Core 2 GlcNAc-T inhibitors |
| US7998943B2 (en) | 2005-07-06 | 2011-08-16 | Btg International Limited | Core 2 GlcNAc-T inhibitors III |
| EP2049122A4 (en) * | 2006-08-03 | 2011-05-18 | Oncology Res Int Ltd | Methods and compositions for inhibiting angiogenesis |
| JP2010500287A (en) * | 2006-08-03 | 2010-01-07 | オンコロジー リサーチ インターナショナル リミテッド | Methods and compositions for inhibiting angiogenesis |
| EP2049122A1 (en) * | 2006-08-03 | 2009-04-22 | Oncology Research International Limited | Methods and compositions for inhibiting angiogenesis |
| JP2013241427A (en) * | 2006-08-03 | 2013-12-05 | Oncology Research Internatl Ltd | Method and composition for inhibiting neoangiogenesis |
| WO2008014564A1 (en) | 2006-08-03 | 2008-02-07 | Oncology Research International Limited | Methods and compositions for inhibiting angiogenesis |
| CN100439511C (en) * | 2006-11-07 | 2008-12-03 | 天津大学 | Process for catalytic extraction of yam saponin by using modified cellulase |
| JP2015151344A (en) * | 2014-02-12 | 2015-08-24 | 株式会社アンチエイジング・プロ | Method for producing dioscorea japonica extract |
| WO2023040094A1 (en) * | 2021-09-18 | 2023-03-23 | 海南鑫开源医药科技有限公司 | Composition having effect of inhibition of tumor cell activity and application of composition |
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|---|---|
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